Throughout this application various patents and other publications are referred to by number in parenthesis. Full citations for the references may be found at the end of the specification. The disclosures of these references and all patents, patent application publications and books referred to herein are hereby incorporated by reference in their entirety into the subject application to more fully describe the art to which the subject invention pertains.
Bacterial infection and sepsis are the most common causes of death in the intensive care unit, annually claiming >225,000 victims in the U.S. alone. The pathogenesis of sepsis remains poorly understood, but is attributable to dysregulated systemic inflammation propagated by innate immune cells (IMCs) in response to microbial infections (1,2) and is partly attributable to dysregulated inflammatory responses sustained by proinflammatory mediators (e.g., HMGB1, CIRP, and NO). The seminal discovery of HMGB1 as a late mediator of lethal systemic inflammation (LSI) (Wang et al., Science, 285: 248-51, 1999) has prompted an investigation of the intricate mechanisms underlying the pharmacological modulation of HMGB1 secretion.
The present invention addresses the need for improved pharmacological treatment of sepsis, including by modulation of HMGB1 secretion via hemichannel activity.